Field of the Invention
The invention relates to compositions and methods for treating estrogen-resistant breast cancer cells.
Background of the Invention
Estrogen receptor-alpha (ER-α) is a member of the nuclear receptor superfamily of ligand activated transcription factors, characterized by: an N-terminal transactivation domain (AF-1), a conserved C-terminal activation domain (AF-2), which overlaps with the ligand binding domain (LBD), a sequence-specific DNA-binding domain (DBD), and a hinge region located between the DBD and AF-2 regions.
Most breast cancers (BCs) (≅70%) are initially estrogen receptor-positive (ER+) and thus potentially suitable for anti-estrogen therapy. Despite being ER+, 50% of patients with advanced breast cancer who receive Tamoxifen (Tam) fail to respond, and all patients with metastatic breast cancer eventually develop resistance to Tam. In addition, many patients (≅40%) who receive Tam as adjuvant therapy will relapse and die of disease. The causes of resistance to different anti-estrogens are not identical, but cross-resistance is common. In most cases of acquired anti-estrogen (E2) resistance, breast cancer cells retain ER and thus may be amenable to novel approaches to target ER.
BRCA1 is a strong inhibitor of E2-stimulated ER-α activity via a direct physical interaction with the AF-2 activation domain of ER-α. In mice, BRCA1 expression is widespread, but it is especially increased in rapidly proliferating cells in compartments that are also undergoing differentiation, including mammary epithelial cells during puberty and pregnancy. BRCA1 also represses ligand-independent activation of ER-α, since BRCA1-siRNA can stimulate ER-α activity in the absence of estrogen. This finding suggests that the endogenous levels of BRCA1 are sufficient to inhibit basal activity levels of ER-α. Further studies have documented that BRCA1 broadly inhibits E2-stimulated gene expression and blocks E2-stimulated proliferation of ER-α positive human breast cancer cells. BRCA1 has been detected at the estrogen response element site of estrogen-regulated promoters (pS2 and cathepsin D), and exposure to E2 causes a rapid loss of BRCA1 from this site. Various breast cancer-associated BRCA1 mutations abrogate or greatly lessen the ability of BRCA1 to inhibit ER-α, suggesting that this function is essential for breast cancer suppression. Finally, it has recently been shown BRCA1 can inhibit the activity of aromatase (CYP19A1), a cytochrome P450 enzyme that mediates the conversion of androgens into estrogens, in epithelial cells and adipocytes.
Mutations of the BRCA1 gene account for about half of all hereditary breast cancer. In 30-40% of sporadic breast cancer, BRCA1 expression is absent or reduced, suggesting a wider role in breast cancer. While many studies on BRCA1 focus on its roles in DNA repair, it also has a major role in regulating ER activity, loss of which confers hypersensitivity to E2 and mammary cancer development in mice. BRCA1 knockdown stimulates the ER agonist activity of Tam, and Tam promotes mammary cancer development in BRCA1-deficient mice. In addition, BRCA1-siRNA can cause Tam-resistance due to altered recruitment of co-regulators by ER. These observations suggest that the early stages of BRCA1-dependent mammary tumorigenesis could be E2-dependent, and thus it may be possible to prevent or treat BRCA1-mutant breast cancers using an agent that can mimic the ability of BRCA1 to inhibit ER-α activity.